Stable oily preparations of epithio-steroids

ABSTRACT

STABLE OILY PREPARATION OF EIPTHIO-STEROIDS USEFUL AS A PHARMACETUICAL OR VETERINARY MEDICINE IN THEIR STRONG ANTI-PROGESTIONAL, ANTI-ESTROGENIC MYOGENIC, ANTI-LIPEAMIE, ANDROGENIC, AND OTHER HARMONAL ACTIVITIES ARE PREPARED BY ADDING AN EPITHIO-STEROID TO AN OIL HAVING A LOW PEROXIDE VALUE.

1973 SHOKEI FUJISAWA 3,754,086

STABLE OILY PREPARATIONS OF EPITHIO-STEROIDS Filed June 7, 1971(POV=1.0)

80 (POV=6.0)

7O E a X l l l 0 2 4 6 8 10 (WEEKS) SHOKEI FUJISAWA, Inventor AttorneysUnited States Patent 3,754,086 STABLE OILY PREPARATIONS 0FEPITHlO-STEROIDS Shokei Fujisawa, Etamishi, Japan, assignor to Shionogi81 Co., Ltd, Osaka, Japan Filed June 7, 1971, Ser. No. 150,529 Claimspriority, application Japan, June 8, 1970,

45/ 19,279, 45/ 19,280 Int. Cl. C07c 173/00 US. Cl. 424-441 35 ClaimsABSTRACT OF THE DISCLOSURE Stable oily preparations of eipthio-steroidsuseful as a pharmaceutical or veterinary medicine in their stronganti-progestational, anti-estrogenic myogenic, anti-lipeamic,androgenic, and other hormonal activities are prepared by adding anepithio-steroid to an oil having a low peroxide value.

This invention relates to stable oily preparations of epithio-steroidsand to a process for preparing the same. The oily preparations ofepithio-steroids comprise essentially an epithio-steroid and an oilhaving a low peroxide value (the peroxide value hereinafter referred toas POV represents amount in mg. of active oxygen in 100 g. of oil). Saidpreparations can be prepared by adding an epithio-steroid to an oilhaving a low POV. The prepara tions of the present invention are usefulas a pharmaceutical or veterinary medicament, because they show stronganti-progestational, anti-astrogenic, myogenic, anti-lipeamic,androgenic, or other hormonal activity.

The epithio-steroids available in the present invention are androstane,pregnane, estrane, cholane, cholestane and other similar steroids,having an epithio group at the position 1,2; 2,3; 3,4; 4,5; 5,6; 6,7;11,12; 14,15; 15,16; or 16,17 of the steroid nucleus. Although theepithiosteroids, e.g. 201,3wepithio-androstan-175-ols show stronganabolic, anti-estrogenic, and anti-fertility activities [tetrahedron,21, 329 (1965)], their practical uses are considerably limited, becausethey cannot be stored for a long time. The same is substantially truefor other epithio-steroids. It was believed that such instability wasprobably due to less resistance of the epithio group to acids at theposition 201,301 of the steroid nucleus. During the course ofinvestigation on an oily preparation, the present inventor found thatthe stability of an epithiosteroid in oil greatly depends on the lotnumber of the preparation. As the result of various studies, it has beenconfirmed that the epithio-steroid contained therein is decomposed bythe action of peroxides in the oil used. Usually, oils in market have avariety of high POV of 38, and their POV turns to higher than 100 by theautoxiclation after exposed to air for a long time. It is therefore verymuch difficult to prepare a stable and long-acting preparation of saidepithio-steroid by using an oil having a high POV. In this connection,the present inventor has succeeded in reducing a high POV to a low oneby treating the oil with an active adsorbent. Thus, stable oilypreparations of the epithio-steroids can be prepared by using an oilhaving a low POV. The present invention has been completed on the basisof these observations.

As mentioned above, the epithio-steroids available in this invention areandrostane, estrane, pregnane, cholane, cholestane, and other similarsteroids, having an epithio group at the position 1,2; 2,3; 3,4; 4,5;5,6; 6,7; 11,12; 14,15; 15,16, or 16,17 of the steroid nucleus. Theseepithio-steroids may have substituent(s) such as lower alkyl, loweralkenyl, acyloxy, alkoxycycloalkyloxy, cycloalkenyloxy, hydroxy, oxo,ketal, carboxyl, ester, halogen,

or unsaturated double bond; and they may further include nororhomo-derivative thereof. Typical examples of said epithio-steroid are asfollows:

201,301-epithio-501-pregnane,

201,301-epithio-501-estrane,

201,301-epithio-5fl-cholane,

201,301-epithio-5fl-cholanic acid methyl ester,

201,301-epithio-501-chloestane,

2,8,35-epithio-501-androstan--01,

201,301-epithio-501-androstan-175-01,

211,300-epithio-501-androstan-17,8-01 acetate,

201,301-epithio-501-androstan-17B-ol propionate,

201,301-epithio-501-androstan-17fi-o1 valerate,

201,3 01-epithio-501-androstan-17,8-01 caprylate,

211,301-epithio-501-androstan-175-01 enanthate,

201,301-epithio-501-androstan-176-01 phenylpropionate,

201,301-epithio-501-androstan-17,3-01 benzoate,

201,3 01-epithio-2fl-methy1-501-androstane,

201,301-epithio-101-methyl-501-androstan-175-01,

25,3B-epithio-101-methyl-501-androstan-17pol,

201,300-epithio-101-methyl-501-androstan-17/3-01 acetate,

201,3 01-epithio-3j3-methyl-501-androstan-17B-ol,

201,301-epithio-701-methyl-501-androstan-1718-01,

201,3 00-epithio-8,8-methyl-501-androstan-17B-ol,

201,301-epithio-1701-methyl-501-androstan-175-01,

201,3 01-epithio-1701-ethyl-501-androstan-17fi-ol,

201,3 01-epithio-1701-vinyl-501-androstan-1713-01,

201,301-epithio-1701-ethynyl-501-androstan175-01,

201,301-epithio-18-methyl-501-androstan-175-01,

201,3 01-epithio-17-methylene-5 01-androstane,

201,301-epithio-501-androstane-701,17B-diol,

201,301-epithio-501-androstane-6/8,17fl-diol,

201,3 01-epithio-17B- l-cyclopentenyl) oXy-501-androstane,

201,3 01-epithio-17fll-cyclohexenyl oxy-S a-androstane,

201,301-epithio-17B-(1-methoxycyclopentyl)oxy-501- androstane,

201,3 01-epithio-175- l-methoxycyclohexyl) oxy-501- androstane,

201,3 01-epithio-17B-( l-methoxycycloheptyl) oXy-501- androstane,

201,3 01-epithio- 17,6-( l-ethoxycyclopentyl) oXy-501- androstane,

201.,301-epithio-17p-( l-ethoxycyclohexyl) oxy-501- androstane,

201,301-epithio-501-androstan-17-one,

101,201-epithio-A-nor-501-androstan-17B-ol,

201,301-epithio-17-methyl-D-homo-501-androstan-175-01,

35,4;8-epithio-501-androstan-175-01,

201,3 01-epithio-501-androst-9(11)-en-17}8-ol,

201,301-epithio-501-androst-6-en-17 3-01,

201,301-epithio-501-andr0st-6-en-17B-ol acetate,

16B,17,8-epithio-4-androsten-3-one,

201,301-epithio-501-estran-17 3-01,

2B,3,9-epithio-S01-estran-176-01 acetate,

200,301-epithio-501-pregnan-20-one,

201,3 a-epithio-l 1,20-dioxo- 17 01-acetyloxy-5 a-pregnane,

201,3 01-epithio-1 1,20-dioxo-1701-hydroxy-501-pregnane,

201,3 00-epithio-1701-acetyloxy-501-pregnan-20-one,

2013 01-epithio-1701,21-dihydroxy-501-pregnan-11,20-dione,

201,300-epithio-2 l-acetyloxy-1701-hydroxy-501-pregnane- 11,20-dione,

2013 01-epithio-1701,21-dihydroxy-501-pregnane-11,20-dione,

20,3 01-epithio-901-fluoro-1 1,8,1701-dihydroxy-501-pregnan- 20-one,

1 101,1201-epithio-501-pregnane-3 5,2001-dio1 and 145, 1 5 ,6-epithio-3fl-hydroxy-S 13, 1 4/S-card-2O (22) -enolide.

They can be prepared according to the methods described as inTetrahedron, 21, 329 (1965) and Ann. Rept.

Shionogi Res. Lab., 19, 1-19 (1969).

The oils in this invention are derived from those of animal, vegetable,and/ or synthetic sources commercially available to make many oilypreparations. As example of the oils are vegetable oils (e.g. sesameoil, olive oil, cottonseed oil, corn oil, peanut oil, castor oil, wheatgerm oil, rice-bran oil, palm oil, sunflowerseed oil, linseed oil, soyabean oil), alkyl esters of fatty acids wherein the alkyl moiety containsup to 10 carbon atoms, and the fatty acid contains 6-18 carbon atoms(e.g. methyl laurate, ethyl laurate, isopropyl laurate, butyl laurate,methyl myristate, ethyl myristate, isopropyl myristate, butyl myristate,isopropyl palmitate, butyl palmitate, amyl palmitate, isopropylstearate, butyl stearate, decyl oleate, diisopropyl adipate), glyceridesof fatty acids wherein the fatty acid contains 8-10 carbon atoms (e.g.glyceryl monocaprylate, glyceryl dicaprylate, glycerely tricaprylate,glyceryl monoperalgonate, glyceryl diperalgonate, glyceryltriperalgonate, glyceryl monocaprate, glyceryl dicaprate, glyceryltricaprate) and mixture thereof, among which sesame oil is the mostpreferable one. The oils available in this invention must have a lowPOV, preferably -2.5. As mentioned above, the oils in market usuallyhave a high POV of 3-8, and it is therefore necessary to reduce the POVto a low one within a POV range of 0-2.5, before use. For this purpose,the oils having a high POV are treated with an adsorbent (e.g. activatedclay, acid clay, activated terra abla, acid terra abla, alumina, silicagel, talc, activated carbon). Among them the clay is most preferablyemployed. More particularly, the desired oil having a preferable POV canbe prepared by mixing together said oil and said adsorbent in an inertatmosphere such as nitrogen or helium, and filtering the resultingmixture. The treatment with the adsorbent is carried out at roomtemperature preferably for 0.5-2 hours, or if necessary, by gentleheating (about 40-70 0.), where the preferable amount of adsorbent is-15 w./w. percent of the oil. The oil thus obtained is to have a low POVof 0-2.5. The POV was determined by iodometric titration where potassiumiodide was added to the oil, and the liberated iodine was titrated withsodium thiosulfate reagent.

According to the present invention, the stable oily preparations of theepithio-steroids can be prepared simply by dissolving said steroid in anoil having a low POV at about room temperature, or if necessary, bygentle heating (about 40-70 C.). It is preferred to effect the procedurein an inert atmosphere, particularly a nonoxidative atmosphere such asnitrogen or helium. The preparations so stabilized can be stored forextended period without appreciable loss of their bio-activity.

For example, the figure shows the influence of peroxide in 4 types ofsesame oil on the stability of 2a,3a-epithio- 5a-androstan-17fi-o1 at 60C. It is apparently shown that the preparation of this invention usingsesame oil having a low POV (1.0) is distinctly more stable duringlonger period than that prepared by the use of commercial sesame oilhaving a higher POV.

The preparations of the present invention are preferably used in thedosage form of injections, and they may be applied to other conventionaldosage forms such as capsules or the like, by using the presentinventive conception and modes known to those skilled in the art. Theymay contain suitable antiseptics, bacteriostats, and/or preservatives.The preparations may be used for the treatment of malnutrition, recoveryfrom emaciation, convalescence, senility, wasting diseases, anddisorders of nutrition, promotion of growth of immature infant,promotion of granulation and protein metabolism, increase in bodyweight, stimulation of apetite, and for the treatment of diseases orconditions demanding anabolic agents, or for implantation inhibition,mastopathy, mammary cancer, endometriosis, regulation of conception,corpulency, etc., to humans, and/or veterinary, and poultry uses. Theycan be administered orally or parenterally in the aforementioned dosageform, where the active epithiosteroid is contained in such amounts as topermit a dosage of 1 to 500 mg. per kg. of body weight for a day. Theadministration is as often as required by the physicians or veterinaryindication.

The following examples are given only by way of illustration and are notintended as limitations of the present invention, many apparentvariations of which are possible without departing from the spirit andscope thereof.

In the working examples, the amount of remaining epithio-steroid wasdetermined in the following method. Two-ml. of the solution (1%) waspipetted into a 20-ml. messfiask and diluted with ethyl ether-ether (1:1by volume). To a 5-ml. aliquot of the diluted solution was added 10 ml.of 0.004 M mercuric acetate. After the mixture was allowed to stand for4 minutes with occasional stirring, 10 m1. of 0.01 N hydrochloric acidwas added and the mixture was titrated potentiometrically with 0.002 Mmercuric acetate. Titration was carried out along with a blank runconcurrently.

EXAMPLE 1 20,3OL-epithiO-Sa-andmstan-175-01 (1 g.) is dissolved in atreated sesame oil ml, POV=0.4) at 40-50 C. and the solution is cooledto room temperature. An additional quantity of the sesame oil is addedto the solution to make a total volume of 100 ml. After the oilysolution is submitted to bacterial filtration, the resulting solution isaseptically subdivided and poured into ampules in a nitrogen stream.

The amount of remaining epithio-steroid in the preparation steroid for afixed period at room temperature was determined as shown below.

Month: Percent remaining 6 96.3

On the contary, the amount of remaining epithio-steroid in thepreparation obtained by using a commercial sesame oil (POV=6.0) was89.6% after 14 weeks storage under the same condition.

In the same manner by using treated peanut oil (POV=0.4), cottonseed oil(POV=0.5), corn oil (POV=0.8), olive oil (POV=0.4), castor oil (POV:1.0), glyceryl monocaprylate (POV=0.1), and isopropyl myristate(POV=0.1) in place of the sesame oil, stable oily preparations arerespectively obtained.

EXAMPLE 2 Month: Percent remaining 2 97.0

Further, the amount of remaining steroid in the preparation prepared inthe same manner as above, but by using the purified sesame oil (POV=2.2)in place of the sesame oil having a POV of 0.1, was 96.3%, 96.0%, and93.5% respectively after 4, 12 and 24 months storage.

To the contrary, when a preparation comprising said epithio-steroid andanother lot of sesame oil (POV=6.0) was stored for comparison at roomtemperature for 14 weeks, the amount of remaining steroid was EXAMPLE 3202,30: epithio 175 (l-methoxycyclopentyl)oxy-5aandrostane (1 g.) isdissolved in a treated sesame oil (80 ml., POV=0.4) at 40-50 C. and thesolution is cooled to room temperature. An additional qauntity of thesesame oil is added to the solution to make a total volume of 100 ml.The solution is submitted to bacterial filtration, and the filtrate isaseptically subdivided and poured into ampules in a nitrogen stream.

The potency of the epithio-steroid in the preparation remains unchangedeven after 6 months storage.

EXAMPLE 4 2a,3a-epithio-5a-androstan-175-01 enanthate (5 g.) isdissolved in a purified sesame oil (80 ml., POV=0.2) by gentle heating(4050 C.) and the solution is cooled to room temperature. An additionalquantity of the sesame oil is added to the solution to make a totalvolume of 100 ml. The mixture is submitted to bacterial filtration andthe filtrate is aseptically subdivided and poured into ampules in anitrogen stream. The oily preparation thus obtained is stable for ratherlonger period.

EXAMPLE 5 2a,3a-epithio-l7a-methyl-5a-androstan-17,8-01 (1 g.) isdissolved in a sesame oil (80 ml., POV=0.4) at 4050 C. and the solutionis cooled to room temperature. An additional quantity of the sesame oilis added to the solution to make a total volume of 100 ml. The solutionis submitted to bacterial filtration, and the resulting solution isaseptically subdivided and poured into ampules in a nitrogen stream.

The epithio-steroid in the preparation is stable during extended period.

EXAMPLE 6 20:,3 u-epithio-l 7,211-dihydroxy-5a-pregnane-1 1,20-dione (1g.) is dissolved in a kind of sesame oil (80 ml., POV=0.4) at 4050 C.and the solution is cooled to room temperature. An additional quantityof the sesame oil is added to the solution to make a total volume of 100ml. The solution is submitted to bacterial filtration, and the resultingsolution is aseptically subdivided and poured into ampules in a nitrogenstream.

The epithio-steroid in the preparation is very stable and durable forextended period.

EXAMPLE 7 2a,3a-epithio-Su-androst-6-en-1713-01 (1 g.) is dissolved in apurified sesame oil (80 ml., POV=0.4) at 4050 C. and the solution iscooled to room temperature. An additional quantity of the sesame oil isadded to the solution to make a total volume of 100 ml. The solution issubmitted to bacterial filtration, and the resulting solution isaseptically subdivided and poured into ampules in a nitrogen stream.

The epithio-steroid in the preparation is very durable for extendedperiod.

In the same manner as above, but using other epithiosteroids ashereinbefore disclosed, corresponding stable and durable preparationsare obtained.

6 EXAMPLE 9 A sesame oil (20 g., POV=5.96) is placed in a -ml. fournecked flask and to this is added activated clay (2.0 g.). The mixtureis stirred at room temperature for 2 hours in a nitrogen stream and thenfiltered. The POV of the resulting oil is found to be 0.04. When thetreatment is performed at 40 C., 60 C., or 70 C. in the same manner asabove, the POV of the resulting oil is found respectively to be 0.05,0.02, or 0.03.

An oil having a low POV is prepared in the same manner as above, usingcottonseed oil, olive oil, peanut oil, corn oil, castor oil, glycerylmonocaprylate, or isopropyl myristate in place of the sesame oil.

EXAMPLE 10 A commercial sesame oil (20 g., POV=7.38) is placed in a100-ml. four necked flask and to this is added activated clay (2.0 g.).The mixture is stirred at 70 C. for 30 minutes in a nitrogen stream andfiltered. The POV of the oil thus obtained is found to be 0.07.

When the treatment is performed for 1, 1.5 or 20 hours,

--the respective POV of the resulting oils is found to be EXAMPLE 11 Acommercial sesame oil (20 g., POV=5.10) is placed in a 100-ml. fournecked flask and to this is added acid clay (2.0 g.) The mixture isheated at 70 C. for 1.5 hours with stirring in a nitrogen stream, andfiltered. The POV of the resulting oil is found to be 0.4.

EXAMPLE 13 Sesame oil having a low POV is prepared by the treatment withalumina in the same manner as that in Example 10.

EXAMPLE 14 A solution in oil for intramuscular injection, composed of 10mg. of 2a,3ot-epithio-17B-(l-methoxycyclopentyl) oxy-5a-androstane in 1ml. of sesame oil having a low peroxide value is prepared according tothe method as in Example 3 and administered once or twice a Week to apatient, e.g. a woman in childbed.

EXAMPLE 15 A capsule, containing a solution of 2.5 mg. of20,3aepithio-(l-ethoxycyclopentyl)oxy-5a-androstane in 0.25 ml. ofsesame oil having a low peroxide value is given orally three times a dayto a patient who is suffering e.g. from malnutrition.

What we claim is:

1. An oily preparation comprising essentially an epithio-steroid thatdecomposes by the action of peroxide in oils which undergo autoxidationafter exposure to air and an oil having a low peroxide value asstabilizer therefor.

2. An oily preparation according to claim 1, wherein the oil has aperoxide value of 0-2.5.

3. An oily preparation according to claim 1, wherein the epithio-steroidis a member selected from the group consisting of androstane, pregnane,estrane, cholane, and cholestane, having an epithio 'group at position1,2; 2,3; 3,4; 4,5; 5,6; 6,7; 11,12; 14,15; 15,16; or 16,17 of thesteroid nucleus and having optional and intact substituent(s) selectedfrom the group consisting of lower 20:,3 a-epithio-a-androstan-175-o1benzoate,

2a,3 tat-epithio-1a-methyl-5a-androstan-175-01,

25,3 5-epithio- 1 a-methyI-Su-androstan- 175-01,

2a,3ot-epithio-1a-methyl-Sa-androStan-175-01 acetate,

20:,3 a-epithio-35-methyl-Su-androstan- 175-01,

2a,3a-epithio-7u-methyl-5a-androstan- 175-01,

2oz,3a-epithio-85-methyl-5 u-androstan- 175-01,

2a,3 u-epithio- 1 7a-methyl-5 a-androstan-17 5-01,

20:,3 ot-epithio-17a-ethyl-5 a-androstan-17 5-01,

2a,3a-epithio-17u-vinyl-5wandrostan-175-01,

2a,3 a-epithio-17a-ethynyl-5a-androstan-175-01,

2u,3a-epithio-1 8-methyl-5a-androstan- 175-01,

2a,3 a-epithio-17-methylene-5 tit-androstane,

20:,3 a-epithio-5a-androstane-7u, 175-diol,

20:,3 a-epithio-Su-androstane-65, 175-dio1,

2a,3a-epithio-175-( l-cyclopentenyl oXy-Swandrostane,

20:,3 a-epithio-l75- l-cyclohexenyl) oxy-5a-androstane,

2a,3 a-epithio-l75-( l-methoxycyclopentyl) oxy-5aandrostane,

2a,3a-epithio- 175- l-methoxycyclohexyl) oxy-5aandrostane,

20,3 a-epithio-175- l-methoxycycloheptyl)oxy-5aandrostane,

2a,3a-epithio- 17 5- l-ethoxycyclopentyl) oxy-5 ozandrostane,

2m,3 u-epithio- 175- l-ethoxycyclohexyl) oxy-Saandrostane,

20:,3 a-epithio-5a-androstan-17-one,

1a,2a-epithio-A-nor-5u-androstan-175-01,

2a,3a-6pithi0- 17-methyl-D-homo-5u-androstan- 175-01,

3 5,45-epithio-5 a-androstan-175-ol,

201,3 aepithio-5a-androst-9(11)-en-175-ol,

20:,3 a-epithio-5u-androst-6-en-175-01,

165, 175-epithio-4-androsten-3-one,

211,3a-epithio-5a-estran-175-ol,

25,35-epithio-5a-estran-175-01 acetate,

2a,3a-epithio-5a-pregnau-20-one,

2a,3a-epithio-11,20-dioxo-17a-acetyloxy-5a-pregnane,

20:,30L-6Pii1hiO-1 1,20-diOXO-17oc-hYd1'OXY-5 a-pregnane,

211,3a-epithio-17a-acetyloxy-Swpregnan-20-one,

2u,3ot-epithio-17a,21-dihydroxy-5a-pregnan-l 1,20-di0ne,

204,3 a-epithio-Z1-acetyloxy-17a-hydroxy-5 a-pregnane- 11,20-dione,

2a,3 u-epithio-17a,21-dihydroxy-5u-pregnane-11,20-one,

l1a,12a-epithio-Sa-pregnane-35,20u-diol and145,155-epithio-35-hydroxy-55,145-card-20(22)-enol-ide.

23. Process according to claim 18, wherein the oil is a member selectedfrom the group consisting of vegetable oil, alkyl ester of fatty acid,glyceride of fatty acid, and mixture thereof.

24. Process according to claim 23, wherein the vegetable oil is a memberselected from the group consisting of sesame oil, olive oil, cottonseedoil, corn oil, peanut oil, castor oil, wheat germ oil, rice-bran oil,palm oil, sunfiowerseed oil, linseed oil, and soya bean oil.

25. Process according to claim 23, wherein the alkyl ester of fatty acidis a member selected from the group consisting of methyl laurate, ethyllaurate, isopropyl 10 laurate, butyl laurate, methyl myristate, ethylmyristate, isopropyl myristate, butyl myristate, isopropyl palmitate,butyl palmitate, amyl palmitate, isopropyl stearate, butyl stearate,decyl oleate, and di-isopropyl adipate.

26. Process according to claim 23, wherein the glyceride of fatty acidis a member selected from the group consisting of glycerylmonocaprylate, glyceryl dicaprylate, glyceryl tricaprylate, glycerylmonoperalgonate, ylyceryl diperalgonate, glyceryl triperalgonate,glyceryl monocaprate, glyceryl dicaprate, and glyceryl tricaprate.

27. Process for preparing an oily preparation of20:,3aepithio-Sa-androstan--01, which comprises adding saidepithio-steroid to sesame oil having a peroxide value of 0-2.5 in aninert non-oxidative atmosphere.

28. Process for preparing an oily preparation of 20:,304-epithio-5a-androstan-175-01 propionate, which comprises adding saidepithio-steroid to sesame oil having a peroxide value of 02.5 in aninert non-oxidative atmosphere.

29. Process for preparing an oily preparation of20:,3ozepithio-175-(l-methoxycyclopentyDoxy 5oz androstane, whichcomprises adding said epithio-steroid to sesame oil having a peroxidevalue of 0-2.5, in an inert non-oxidative atmosphere.

30. Process for preparing an oily preparation of2a,3aepithiQ-Sa-androstan-175-01 enanthate, which comprises adding saidepithio-steroid to sesame oil having a peroxide value of 0-2.5, in aninert non-oxidative atmosphere.

31. Process for preparing an oily preparation of 2u,3aepithio-17a-methy15a androstan-175-ol, which comprises adding said epithio-steroid tosesame oil having a peroxide value of 0-2.5, in an inert non-oxidativeatmosphere.

32. Process for preparing an oily preparation of 201,30:-epithio-17a,21-dihydroxy 5a pregnane 11,20 dione, which comprises addingsaid epithio-steroid to sesame oil having a peroxide value of 0-2.5, inan inert non-oxidative atmosphere.

33. Process for preparing an oily preparation of2a,3mepithio-11,20-dioxo 17a acetyloxy-5a-pregnane, which comprisesadding said epithio-steroid to sesame oil having a peroxide value of0-2.5.

34. Process for preparing an oily preparation of2u,3aepithio-5a-androst-6-en-175-01, which comprises adding saidepithio-steroid to sesame oil having a peroxide value of 0-25, in aninert non-oxidative atmosphere.

35. A medicament dosage unit form for human and veterinary use,containing an eifective dosage amount of 1 or more epithio-steroids thatdecompose by the action of peroxide in oils which undergo autoxidationafter exposure to air and as the essential stabilizing carrier thereforan oil having a low peroxide value.

References Cited UNITED STATES PATENTS 3,670,080 6/1972 Hirata 424-241SHEP K. ROSE, Primary Examiner US. Cl. X.R.

